A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449

Phase 1

Completed

Conditions: Asthma

Interventions: Drug: AZD0449
Drug: Placebo

Registration Number: NCT03766399

Lead Sponsor: AstraZeneca

Brief Summary: This will be a Phase I, first in human (FIH) study consisting of the following parts: Part 1a (SAD), Part 1b (IV Cohort), Part 2 (Multiple ascending dose (MAD), and Part 3 dry-powder inhalation (DPI)/ Proof of mechanism (PoM). Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study performed at a single study center. Part 1b, will be an open-label, single-dose, single-cohort study. It will follow a 2-stage design in the way that participants from Part 1a will be selected for the IV Cohort in Part 1b. Part 2 of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design and study performed at 3 study centers. Part 3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. The expected duration of each subject in Part 1a of the study is up to 36 days and up to 53 days for subjects participating in Part 1b. The expected duration of each participant in Part 2 is up to 52 days and Part 3 is up to 55 days.

Detailed Description: This will be a Phase I, consisting of the following parts: Part 1a, Part 1b, Part 2a/b, Part 3a/b. Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study performed at a single study center. Six inhaled dose levels of AZD0449 nebulized suspension are planned to be investigated in 6 cohorts. Depending on emerging safety and PK data, up to 3 additional inhaled dose levels (cohorts), within the pre-specified dose range, may be added at the discretion of the Sponsor. Within each cohort, 6 volunteers will be randomized to receive an inhaled dose of AZD0449 nebulized suspension and 2 volunteers will be randomized to receive inhaled placebo. Intravenous (IV) dosing in Part 1b of the study will be initiated after the completion of cohort 6 in Part 1a or (if Part 1a is completed with less than 6 cohorts) after completion of the last cohort in Part 1a. Part 1b, will be open-label and consist of 2 dose cohorts (IV 0.090 mg and 0.360 mg) and be conducted in 12 healthy volunteers. Six (6) volunteers will be selected for the first IV dose cohort in Part 1b following a 2-stage design. If Part 1b cannot be completed with 6 volunteers from Part 1a or if some of the data are considered not evaluable, up to 6 additional naïve volunteers may be enrolled. A second IV dose cohort in Part 1b will be initiated after the evaluation of the PK and safety results from all cohorts in Part 1a and completion of the first IV dose cohort in Part 1b. The second IV dose cohort will consist of 6 healthy volunteers who have not previously participated in the study (naïve volunteers). Part 2a/b of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design study performed at approximately 3 study centers. Part 2a will include cohorts 1 and 2, each comprising of 9 patients with mild asthma. Within each of these cohorts 6 patients will be randomized to receive AZD0449 nebulized suspension and 3 patients randomized to receive placebo. Additional cohorts with 9 patients could be added to study PK, PD and safety for doses lower than 1.2 mg or up to 5 mg. Part 2b will consist of 1 cohort of 8 healthy volunteers; 6 volunteers will be randomized to receive AZD0449 nebulized suspension and 2 volunteers will be randomized to receive placebo. Part 3a/b of the study will be initiated after the completion of Part 2b. Part 3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. Part 3 will be conducted in up to 36 patients with mild asthma (Part 3a) and 8 healthy volunteers (Part 3b, optional). Part 3a will consist of 36 patients, where 18 patients will be randomized to AZD0449 DPI and 18 patients to placebo. An Interim Analysis (IA) will be conducted when 9 patients on each arm have completed the study (50% Part 3a). Should new data on the variability of the FeNO measurements emerge at the IA, the sample size in Part 3a could be changed. If the optional Part 3b is conducted, it will comprise 8 healthy volunteers; 6 volunteers will be randomized to AZD0449 DPI and 2 volunteers to placebo.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 131

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1a (SAD) Cohort 1	Placebo	6 participants will receive inhaled dose 1 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 1	AZD0449	6 participants will receive inhaled dose 1 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 2	AZD0449	6 participants will receive inhaled dose 2 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 2	Placebo	6 participants will receive inhaled dose 2 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 3	Placebo	6 participants will receive inhaled dose 3 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 5	Placebo	6 participants will receive inhaled dose 5 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 4	Placebo	6 participants will receive inhaled dose 4 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 5	AZD0449	6 participants will receive inhaled dose 5 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 6	Placebo	6 participants will receive inhaled dose 6 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1b (IV cohort 1)	Placebo	All 6 participants will receive single IV dose of AZD0449 solution.
Part 2a (MAD) Cohort 1	AZD0449	6 participants will receive inhaled dose 7 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.
Part 2a (MAD) Cohort 1	Placebo	6 participants will receive inhaled dose 7 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.
Part 2a (MAD) Cohort 2	AZD0449	6 participants will receive inhaled dose 8 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.
Part 2a (MAD) Cohort 2	Placebo	6 participants will receive inhaled dose 8 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.
Part 2b (MAD/healthy volunteers) Cohort 3	AZD0449	18 healthy volunteers will receive inhaled dose 9 of AZD0449 nebulized suspension and 12 healthy volunteers will receive inhaled placebo.
Part 2b (MAD/healthy volunteers) Cohort 3	Placebo	18 healthy volunteers will receive inhaled dose 9 of AZD0449 nebulized suspension and 12 healthy volunteers will receive inhaled placebo.
Part 3a (DPI/PoM)	AZD0449	18 participants will receive inhaled dose 10 of AZD0449 DPI and 6 participants will receive inhaled placebo.
Part 3a (DPI/PoM)	Placebo	18 participants will receive inhaled dose 10 of AZD0449 DPI and 6 participants will receive inhaled placebo.
Part 1b (IV cohort 2)	AZD0449	6 healthy volunteers will receive single IV dose of AZD0449 solution.
Part 1b (IV cohort 2)	Placebo	6 healthy volunteers will receive single IV dose of AZD0449 solution.
Part 3b (DPI/healthy volunteers)	AZD0449	Part 3b is optional. 8 healthy volunteers; 6 volunteers will receive AZD0449 DPI and 2 volunteers will recieve placebo.
Part 3b (DPI/healthy volunteers)	Placebo	Part 3b is optional. 8 healthy volunteers; 6 volunteers will receive AZD0449 DPI and 2 volunteers will recieve placebo.
Part 1a (SAD) Cohort 3	AZD0449	6 participants will receive inhaled dose 3 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 4	AZD0449	6 participants will receive inhaled dose 4 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1a (SAD) Cohort 6	AZD0449	6 participants will receive inhaled dose 6 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
Part 1b (IV cohort 1)	AZD0449	All 6 participants will receive single IV dose of AZD0449 solution.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events and Serious Adverse Events	From screening up to follow-up visit [Part 1 a (6±1 Days post-dose)] [Part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)]	Safety and tolerability of AZD0449 following inhaled administration of single ascending doses to healthy participants, inhaled nebulized administration of multiple ascending doses to healthy participants and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUCinf)	Part 1b: Day 1	AUCinf of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC(0-24))	Part 1b: Day 1	AUC (0-24) of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Dose Normalized Cmax (Cmax/D)	Part 1b: Day 1	Cmax/D of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Maximum Observed Plasma Concentration (Cmax)	Part 1b: Day 1	Cmax of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast)	Part 1b: Day 1	AUClast of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Volume of Distribution for Parent Drug at Terminal Phase [Intravenous Administration] (λz)	Part 1b: Day 1	Vz of AZD0449 following intravenous administration of a single dose of AZD0449 to healthy volunteers was assessed.
Time to Reach Peak or Maximum Observed Concentration Following Drug Administration (Tmax)	Part 1b: Day 1	tmax of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Terminal Halflife, Estimated as (ln2)/-λz (t½λz )	Part 1b: Day 1	t½λz of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Terminal Rate Constant, Estimated by Loglinear Leastsquares Regression of the Terminal Part of the -Concentrationtime- Curve (λz)	Part 1b: Day 1	λz of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Time of Last Quantifiable Concentration (Tlast)	Part 1b: Day 1	tlast of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Total Body Clearance of Drug From Plasma After Intravascular Administration (CL)	Part 1b: Day 1	CL of AZD0449 following intravenous administration of a single dose of AZD0449 to healthy volunteers was assessed.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events and Serious Adverse Events	From screening up to follow-up visit [Part 1b (6±1 Days post-dose)]	Safety and tolerability of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.
Terminal Halflife, Estimated as (ln2)/-λz (t½λz )	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	t½λz of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Apparent Volume of Distribution for Parent Drug at Terminal Phase [Extravascular Administration] (Vz/F)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	Vz/F of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Terminal Rate Constant, Estimated by Loglinear Leastsquares Regression of the Terminal Part of the -Concentrationtime- Curve (λz)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	λz of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Dose Normalized Cmax (Cmax/D)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	Cmax/D of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Maximum Observed Plasma Concentration (Cmax)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	Cmax of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy participants and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUCinf)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	AUCinf of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy participants and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	AUClast of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy participants and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC(0-24))	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	AUC (0-24) of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Time to Reach Peak or Maximum Observed Concentration Following Drug Administration (Tmax)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	tmax of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	CL/F of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Time of Last Quantifiable Concentration (Tlast)	Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12	tlast of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.
Change From Baseline in 2 Hours Post-dose Fractional Excretion of Nitric Oxide (FeNO)	At Baseline and Day 12	Assessment of anti-inflammatory effect by evaluating change from baseline in FeNO, 2 hours post-dose of AZD0449 in patients with mild asthma was assessed.
Change From Baseline in 2 Hours Post-dose in FeNO (AUC (0-12))	At Baseline and Day 12	Assessment of anti-inflammatory effect by evaluating change from baseline in FeNO (AUC (0-12)), 2 hours post-dose of AZD0449 in patients with mild asthma was assessed.